CN110862375A - Pyrazole compound and pharmaceutical composition and application thereof - Google Patents
Pyrazole compound and pharmaceutical composition and application thereof Download PDFInfo
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
The invention relates to a pyrazole compound, a pharmaceutical composition and an application thereof, wherein the pyrazole compound has a structure shown in a formula (I). Such compounds are useful for inhibiting IRAK family kinases and also for treating diseases caused by IRAK family kinases, such as autoimmune diseases, inflammatory diseases and cancer. The invention also relates to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and to the use of such compounds or pharmaceutical compositions for the preparation of medicaments for the treatment of diseases caused by IRAK family kinases.
Description
Technical Field
The invention belongs to the field of chemical medicines, and relates to pyrazole compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds and application of the compounds or the compositions in preparation of medicines.
Background
The IRAK protein family consists of four members: IRAK1, IRAK2, IRAK3, and IRAK 4. IRAK1 and IRAK4 are active serine/threonine kinases that are key signaling factors downstream of the interleukin receptor-1 (IL-1R) and Toll-like receptor (TLR) signaling pathways and play important roles in innate immunity, while IRAK2 and IRAK3 are pseudokinases. IRAK1 and IRAK4 have been implicated in blood cancers. In certain B cell lymphomas, activation of the TLR/IRAK pathway is often associated with MYD88L265PThe gain-of-function mutations occur simultaneously. This mechanism occurs in Waldenstrom's Macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), and primary effusion lymphoma (1-4). The concentration of IRAK1 was also elevated in partial head and neck squamous cell carcinoma, liver cancer, and triple negative breast cancer (5-7). In a mouse liver cancer model, the IRAK1/4 inhibitor can inhibit the growth of HCC tumors, and has a synergistic effect on the inhibition of the tumors when the inhibitor is used together with sorafenib (7). MYD88/IRAK signaling plays an essential role in the survival of T-cell acute lymphoblastic leukemia (T-ALL) cells (8-9). Activation and overexpression of IRAK1 has a negative prognostic impact in myelodysplastic syndrome (MDS) (8, 10). IRAK1 is overexpressed in Acute Myeloid Leukemia (AML) (11). It was shown that inhibition of IRAK1/4 reduces the proliferation of mixed lineage leukemia rearrangement leukemia cells (12). These studies have well demonstrated that IRAK1 and IRAK4 are targets for the treatment of cancer.
IRAK1 and IRAK4 are also targets for the treatment of autoimmune diseases IRAK4 deletion or genetically modified mice expressing IRAK4 without kinase activity have an impaired immune response to TLR stimulation (e.g., LPS-induced production of TNF α and IL 6) (13). these mice are resistant to experimentally induced arthritis (14), atherosclerosis (15), and MOG-induced encephalomyelitis (16). mice with no IRAK4 kinase activity are resistant to the development of Alzheimer's disease (17). IRAK4 small molecule inhibitors have been shown to inhibit TLR-induced inflammatory signaling in vivo and in vitro (18-19). administration of IRAK4 inhibitors can reduce gout-like inflammation in uric acid-induced peritonitis models (19) and reduce disease in lupus mouse models (20).
The present invention provides novel structural IRAK inhibitors which inhibit IRAK4 kinase activity and are useful for the treatment of autoimmune diseases, inflammatory diseases and cancer.
Citations
1.Jimenez,C.et al.,Leukemia,2013,27,1722-1728.
2.Yang,G.et al.,Blood,2013,122,1222-1232.
3.Ngo,V.N.et al.,Nature,2011,470,115-119.
4.Yang,D.et al.,Proc.Natl.Acad.Sci.USA,2014,111,E4762-4768.
5.Wee,Z.N.et al.,Nat.Commun.2015,6,8746.
6.Adams,A.K.et al.,Oncotarget,2015,6,43395-43407.
7.Cheng,B.Y.et al.,Cancer Res.2018,78,2332-2342.
8.Li,Z.et al.,J.Clin.Invest.2015,125,1081-1097.
9.Dussiau,C.et al.,Oncotarget,2015,6,18956-18965.
10.Rhyasen,G.W.et al.,Cancer Cell,2013,24,90-104.
11.Beverly,L.J.et al.,Oncotarget,2014,5,1699-1700.
12.Liang,K.et al.,Cell,2017,168,59-72e13.
13.Kim,T.W.et al.,J.Exp.Med.2007,204,1025-1036.
14.Koziczak-Holbro,M.et al.,Arthritis Rheum.2009,60,1661-1671.
15.Rekhter,M.et al.,Biochem.Biophys.Res.Commun.2008,367,642-648.
16.Staschke,K.A.et al.,J.Immunol.2009,183,568-577.
17.Cameron,B.et al.,J.Neurosci.2012,32,15112-15123.
18.Tumey,L.N.et al.,Bioorg.Med.Chem.Lett.2014,24,2066-2072.
19.Kelly,P.N.et al.,J.Exp.Med.2015,212,2189-2201.
20.Dudhgaonkar,S.et al.,J.Immunol.2017,198,1308-1319.
Disclosure of Invention
The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure:
wherein the content of the first and second substances,
het ring is a five or six membered heteroaromatic ring;
R1selected from: h, D;
R2and R3Each selected from: h, D, alkyl, halogen, OR ORa;
R4Selected from: COR (continuous operating reference)d,CONRbRc,CO2Rd,SO2RdOr SO2NRbRc;
R5Selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRcAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with 1-3R5aSubstitution;
R5aselected from: h, D, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc. Wherein said alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1-3R5bSubstitution;
R5bselected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc;
Ra,Rb,RcAnd RdEach selected from: h, D, alkyl, alkenyl, alkynyl, cycloakyl, aryl, or heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with 1-4R6Substitution;
R6selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
wherein, R is contained simultaneouslybAnd RcIn the group of (A) RbAnd RcIs singly bound to the N atom of the radical or to the nitrogen atom to which they are bound to form a heterocycloalkyl radical which is unsubstituted or substituted by 1 to 3R7Substitution;
R7selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
m, n, p, q, and y are each independently 1,2, or 3.
Preferably, the compounds provided by the present invention have the structure shown in formula (IA):
wherein the content of the first and second substances,
R4selected from: COR (continuous operating reference)d,CONRbRc,CO2Rd,SO2RdOr SO2NRbRc;
R5Selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRcAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with 1-3R5aSubstitution;
R5aselected from: h, D, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc(ii) a Wherein said alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or 1-3R5bSubstitution;
R5bselected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc;
R8Selected from: h, D, alkyl, halogen, haloalkyl, ORa;
Ra,Rb,RcAnd RdEach selected from: h, D, alkyl, alkenyl, alkynyl, cycloakyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstitutedOr by 1-4R6Substitution;
R6selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
wherein, R is contained simultaneouslybAnd RcIn the group of (A) RbAnd RcIs singly bound to the N atoms of the radicals or to the nitrogen atom to which they are bound to form a heterocycloalkyl radical which is unsubstituted or substituted by 1 to 3R7Substitution;
R7selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
z is 1 or 2.
Detailed Description
The term "halo" or "halogen" in the present invention includes fluorine, chlorine, bromine, and iodine.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), hexyl (e.g., n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 2-dimethylbutyl, 3-ethylpentyl-1, etc.), heptyl (e.g., n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 2-methylhexyl, 3-methylhexyl, 2-dimethylpentyl, 3-dimethylpentyl, 3-ethylpentyl-1, etc.), octyl (e.g., 1-octyl, 2-ethylhexyl, etc.), nonyl (e.g., 1-nonyl), and the like, Decyl groups (e.g., n-decyl, etc.), and the like. In particular, the term "alkyl group" refers to a linear or branched alkyl group having 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, more specifically, a linear or branched alkyl group having 1,2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms, and still more preferably, a linear or branched alkyl group having 1,2, 3, 4, 5, 6 carbon atoms. Unless defined to the contrary, all radical definitions in the present invention are as defined herein.
The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Wherein the alkyl group and halo or halogen are as defined above. Examples of haloalkyl groups include CH2F、CHF2、CF3、C2F5、CCl3And the like.
The term "alkenyl" refers to a hydrocarbyl group having one or more C ═ C double bonds. Examples of alkenyl groups include ethenyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl, 1, 3-pentadienyl, 1-hexenyl, 2-hexenyl, and the like.
The term "alkynyl" refers to a hydrocarbyl group having one or more C ≡ C triple bonds. Examples of alkynyl groups include ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and the like.
The term "cycloalkyl" refers to a non-aromatic carbocyclic ring, including cyclized alkyl, cyclized alkenyl, and cyclized alkynyl groups. Cycloalkyl groups may be monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems, including spirocyclic rings. In certain embodiments, a cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms. The cycloalkyl group may further have 0, 1,2 or 3C ═ C double bonds and/or 0, 1 or 2C ≡ C triple bonds. Also included in the definition of cycloalkyl are those moieties having one or more aromatic rings fused to the cycloalkyl ring (e.g., having a common bond), such as benzo derivatives of pentane, pentene, hexane, hexene, and the like. Cycloalkyl groups having one or more fused aromatic rings may be linked through aromatic or non-aromatic moieties. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, adamantyl, indanyl, tetrahydronaphthyl, and the like.
The term "heterocycloalkyl" refers to a non-aromatic heterocyclic ring in which one or more of the ring-forming atoms is a heteroatom such as O, N, P, or S. Heterocyclyl groups may include monocyclic or polycyclic (e.g. having 2,3 or 4 fused rings) ring systems as well as spirocyclic rings. Examples of preferred "heterocycloalkyl" groups include, but are not limited to: aziridinyl, azetidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and the like. Also included in the definition of heterocycloalkyl are those moieties having one or more aromatic rings (e.g., having a common bond) fused to a non-aromatic heterocycloalkyl ring, such as 2, 3-dihydrobenzofuranyl, 1, 3-benzodioxolyl, benzo-1, 4-dioxacyclohexyl, phthalimidyl, naphthalimide, and the like. Heterocycloalkyl groups having one or more fused aromatic rings can be attached through an aromatic or non-aromatic moiety.
The term "aryl" refers to a monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) aromatic hydrocarbon such as phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like.
The term "heteroaryl" refers to an aromatic heterocyclic ring having at least one heteroatom ring member such as O, N or S. Heteroaryl groups include monocyclic or polycyclic (e.g., having 2,3, or 4 fused rings) ring systems. Any ring-forming N atom in the heterocyclic group may also be oxidized to form an N-oxide. Examples of preferred "heteroaryl" groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 4-thiadiazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and the like.
The term "compound", as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, isotopes.
The compounds of the invention may be asymmetric, e.g. having one or more stereogenic centers. Unless otherwise defined, all stereoisomers, both enantiomers and diastereomers, may be present. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of the racemate or by using chiral synthons (synthons) or chiral reagents.
The compounds of the present invention may also include tautomeric forms. The novel forms of tautomers result from the exchange of a single bond and an adjacent double bond together with the migration of a proton.
The compounds of the invention may also include all isotopic forms of the atoms present in the intermediate or final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.
The invention also includes pharmaceutically acceptable salts of the compounds of formula (I) and formula (IA). Pharmaceutically acceptable salts refer to derivatives of a compound wherein the parent compound is modified by the conversion of an existing base moiety into its salt form, or wherein the parent compound is converted into it by the presence of an acid moietyDerivatives of the compounds modified in the form of salts. Examples of pharmaceutically acceptable salts include, but are not limited to: salts of inorganic or organic acids of basic groups, such as ammonia, or salts of inorganic or organic bases of acidic groups, such as carboxylic acids. The pharmaceutically acceptable salts of the present invention may be synthesized from the parent compounds of formula (I) and formula (IA) by reacting the free base forms of these compounds with 1 to 4 equivalents of the appropriate acid in a solvent system. Suitable salts are described in Remington's pharmaceutical Sciences,17thed., Mack Publishing Company, Easton, Pa.,1985, p.1418 and Journal of Pharmaceutical Science,66,2 (1977).
The compounds of the present invention, as well as pharmaceutically acceptable salts thereof, also include solvate or hydrate forms. In general, the solvate form or hydrate form is equivalent to the non-solvate form or non-hydrate form and is included in the scope of the present invention. Some compounds of the present invention may exist in various crystalline forms or amorphous forms. In general, all physical forms of the compounds are included within the scope of the present invention.
The invention also includes prodrugs of the compounds of formula (I) and formula (IA). A prodrug is a pharmacological substance (i.e., drug) that is derived from the parent drug. Once administered, the prodrug is metabolized in vivo to the parent drug. Prodrugs can be prepared by substituting one or more functional groups present in the compound. Preparation and use of prodrugs can be found in T.Higuchi and V.Stella, "Pro-drugs as Novel Delivery Systems," Vol.14of the A.C.S.Symposium series and Bioreproducible Carriers in Drug Design, ed.Edward B.Roche, American pharmaceutical Association and Pergamon Press, 1987.
In some embodiments, the compounds of the present invention are selected from the following compounds:
n- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-methyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-ethyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-isopropyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (aminomethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (hydroxymethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-hydroxy-2-methylpropyl-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1H-pyrazol-3-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (3- (difluoromethyl) -1- (1- (1-propionylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1-isobutyrylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
(S) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
(R) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide.
In another aspect of the present invention, there is also provided a composition consisting of a compound of formula (I) and formula (IA) or an N-oxide derivative, an individual isomer, or a mixture of isomers thereof, and a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier or excipient. The compositions of the invention may be administered orally, parenterally (by injection), by inhalation spray, topically, rectally, nasally, vaginally, intraperitoneally, or via an implanted reservoir.
In another aspect of the invention, the invention provides a compound of formula (I) and formula (IA) and pharmaceutically acceptable salts for use in inhibiting protein kinases.
In some embodiments, the protein kinase is an IRAK family kinase, particularly an IRAK4 kinase.
In another aspect of the invention, the invention provides compounds of formula (I) and formula (IA) and pharmaceutically acceptable salts for use in the treatment of diseases caused by protein kinases.
In some embodiments, the compounds or compositions of the present invention may be used to treat autoimmune diseases caused by IRAK family kinases, particularly IRAK4 kinase; inflammatory diseases; pain disorders; respiratory, airway and lung diseases; lung inflammation and injury; pulmonary hypertension; gastrointestinal disorders; allergic diseases; infectious diseases; trauma and tissue injury disorders; fibrotic diseases; eye diseases; joint, muscle and bone diseases; skin diseases; kidney disease; diseases of the hematopoietic system; liver disease; oral diseases; metabolic diseases, heart diseases; vascular disease; a neuroinflammatory disorder; neurodegenerative diseases; sepsis; a genetic disease.
In some embodiments, the autoimmune and inflammatory diseases described herein are selected from: systemic Lupus Erythematosus (SLE), lupus nephritis, arthritis, psoriasis, colitis, crohn's disease, atopic dermatitis, liver fibrosis, senile dementia, gout, protein-related periodic syndrome (CAPS), chronic kidney disease or acute kidney injury, Chronic Obstructive Pulmonary Disease (COPD), asthma, bronchospasm, and graft-versus-host disease.
In some embodiments, the compounds or compositions of the present invention may be used to treat diseases of abnormal cellular proliferation, particularly cancer, caused by IRAK family kinases, particularly IRAK4 kinases.
In some embodiments, the cancer of the invention includes breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, cancer of the gastrointestinal tissue, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vaginal cancer, leukemia, multiple myeloma, and lymphoma.
In another aspect of the invention, the compounds of formula (I) and formula (IA) and pharmaceutically acceptable salts of the present invention may be used in combination with one or more other drugs. When used in combination, the compounds of the present invention may act additively or synergistically with the drugs used in combination. The drugs used in combination can be small molecule drugs, monomer clone drugs, fusion protein drugs and anti-influenza DNA drugs.
In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, consisting of the steps of:
A. reacting nitropyrazole carboxylate A-1 with Boc-protected azetidinesulfonate A-2 to obtain A-3, wherein R1Is alkyl, R2Is alkyl or aryl;
B.A-3 with a reducing agent such as diisobutylaluminum hydride DIBAL-H to give aldehyde B-1;
the aldehyde group in C.B-1 is converted to difluoromethyl group using a fluorine reagent such as diethylaminosulfur trifluoride DAST to give C-1;
removing Boc in C-1 with an acid such as trifluoroacetic acid, and performing reductive amination with Boc-protected piperidone to obtain D-1;
E.D-1, wherein L is chlorine or OH, is removed with an acid, such as trifluoroacetic acid, and condensed with an acid chloride, or condensed with an acid with a condensing agent HATU to give E-1;
F.E-1 with a reducing agent, e.g. H2And Pd/C, reducing to obtain an amino compound F-1;
G. pyrazole boronic acid esters G-1 with 6-bromo-2-pyridinecarboxylic acid (X ═ H) or carboxylic acid esters (X ═ alkyl) G-2 over a palladium catalyst, for example Pd (PPh)3)4Coupled, then hydrolyzed with a base (when X ═ alkyl), such as NaOH, to give G-3;
H. the carboxylic acid G-3 is condensed with amino intermediate F-1 using a condensing agent, such as HATU, to provide compound IA of the present invention. If R in IA5When an amino group is present, R of G-3 condensed with F-15With cyano groups in the presence of a reducing agent, e.g. NaBH4/CoCl2/MeOH, reduction to give R5Compound IA containing an amino group;
I. alternatively, amino intermediate F-1 is condensed with pyridine carboxylic acid G-2 using a condensing agent, such as HATU, to provide I-1; then I-1 is reacted with the borate G-1 using a palladium catalyst, e.g. Pd (PPh)3)4Coupling to give compound IA of the invention;
example 1
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.1- (2, 2-difluoroethyl) -4-iodo-1H-pyrazole
In a 100mL round bottom flask, 4-iodopyrazole (5.0g, 25.7mmol), triphenylphosphine (13.5g, 51.4mmol), 2, 2-difluoroethanol (2.1g, 25.7mmol) were dissolved in THF (80 mL). Activated 4A molecular sieves (10.0g) and diisopropyl azodicarboxylate (DIAD, 10.4g, 51.4mmol) were added to the above solution and reacted at room temperature for 6 h. After completion of the reaction, diluted with water, extracted with EtOAc, the combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 4.6g of product in 69% yield. LCMS (ESI) M/z 259(M + H)+。
Step 2 methyl 6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate
1- (2, 2-Difluoroethyl) -4-iodo-1H-pyrazole (2.0g, 7.8mmol), pinacol diboron (4.0g, 15.6mmol), Pd (dppf) Cl were added to a 100mL round bottom flask under nitrogen2(571mg, 0.78mmol), AcOK (2.3g, 23.4mmol) and dioxane (40mL) were reacted at 100 ℃ for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, methyl 6-bromo-2-pyridinecarboxylate (1.7g, 7.8mmol), Pd (PPh) were added to a 100mL round-bottomed flask under nitrogen protection3)4(901mg,0.78mmol),Na2CO3(1.7g, 15.6mmol), dioxane (40mL), H2O (8mL), heated to 80 ℃ and reacted for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 1.3g of product in 62% yield. LCMS (ESI) 268(M + H) M/z+。
Step 3.6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
Methyl 6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate (1.3g, 4.9mmol) was dissolved in MeOH (15mL), and a solution of NaOH (1M 15mL) was added to react at room temperature for 1H. After completion of the reaction, MeOH was concentrated, diluted with water, and extracted with EtOAc. Adjusting pH of water phase to 3 with 4M hydrochloric acid, precipitating solid, filtering, and adding H2O washing to obtain 1.1g of solid with 89% yield. LCMS (ESI) 254(M + H) M/z+。
Step 4. Ethyl 4-nitro-1H-pyrazole-3-carboxylate
4-Nitro-1H-pyrazole-3-carboxylic acid (20.0g, 127.4mmol) was dissolved in EtOH (200mL), cooled in an ice bath, and slowly added dropwise to SOCl2(15mL) and then heated to reflux for 6 h. After the reaction was complete, 5% Na was added2CO3Adjusting the water solution to neutral, distilling under reduced pressure to remove ethanol, diluting the residue with water, extracting with EtOAc, mixing the organic phases, washing with saturated NaCl solution, and collecting anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 22.0g of product in 93% yield. LCMS (ESI) M/z 186(M + H)+。
Step 5. Tert-butyl 3- (p-toluenesulfonyloxy) azetidine-1-carboxylate
In a 150mL round bottom flask, N-Boc-3-hydroxyazetidine (10g, 57.8mmol) was dissolved in CH2Cl2(40mL) was cooled in an ice bath. To the above solution were added p-toluenesulfonyl chloride (11g, 57.8mmol) and pyridine (5.5g, 69.4mmol), followed by reaction at room temperature for 10 h. After the reaction is finished, adding water for dilution, separating liquid, and adding CH into an aqueous phase2Cl2And (4) extracting. The organic phases were combined, in turn with 5% NaHCO3Washing the solution with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 30: 1) to give 13.5g of product in 71% yield.
LCMS(ESI):m/z=328(M+H)+。
Step 6 Ethyl 1- (1- (tert-butylcarbonyl) azetidin-3-yl) -4-nitro-1H-pyrazole-3-carboxylate
In a 500mL three-necked round-bottomed flask, ethyl 4-nitro-1H-pyrazole-3-carboxylate (22.0g, 118.9mmol), DMSO (200mL) and K were added2CO3(19.7g, 142.7mmol), the reaction was stirred at room temperature for 0.5h, then heated to 100 ℃. Then, a DMSO (40mL) solution of tert-butyl 3- (p-toluenesulfonyloxy) azetidine-1-carboxylate (38.9g, 118.9mmol) was added dropwise to the reaction mixture, followed by reaction for 6 hours. After completion of the reaction, diluted with water, extracted with EtOAc, the combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 20.5g of product in 51% yield. LCMS (ESI) M/z 341(M + H)+。
Step 7. tert-butyl 3- (3-aldehyde-4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate
Ethyl 1- (1- (tert-butylcarbonyl) azetidin-3-yl) -4-nitro-1H-pyrazole-3-carboxylate (20.5g, 60.3mmol) in a 500mL three-necked round-bottomed flask equipped with a thermometer under nitrogen2Cl2(200mL) and placed in a dry ice/acetone bath for cooling. Slowly dripping 1M DIBAL-H n-hexane solution (150mL) into the upper solution while maintaining the internal temperature below-65 deg.C, and pouring saturated NH into the upper reaction solution4Cl solution (500mL), filtration after stirring, extraction of the filtrate with EtOAc, combination of the organic phases, washing with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 2: 1) to give 12.6g of product in 71% yield. LCMS (ESI) 315(M + H) M/z2O+H)+。
Step 8 tert-butyl 3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate
In a 250mL round-bottomed flask, tert-butyl 3- (3-aldehyde-4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate (12.6g, 42.6mmol) was dissolved in CH2Cl2(150mL) and placed in an ice-water bath to cool. Diethylaminosulfur trifluoride (DAST, 17.1g, 106.5mmol) was slowly added dropwise thereto, and the reaction was maintained at that temperature for 1 hour. After the reaction is finished, 5% NaHCO is added3The aqueous solution is adjusted to neutrality by CH2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 7.5g of product in 55% yield. LCMS (ESI) M/z 319(M + H)+。
Step 9. tert-butyl 4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylic acid ester
In a 100mL round-bottomed flask, tert-butyl 3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidine-1-carboxylate (5.0g, 15.7mmol) was dissolved in CH2Cl2(50mL), trifluoroacetic acid (10mL) was added and the reaction was carried out at room temperature for 1 h. After the reaction is completed, decreaseThe solvent and trifluoroacetic acid were removed by distillation under pressure. The remainder being dissolved in CH2Cl2(50mL) in Et3The pH was adjusted to 8 with N. To the above solution were added N-Boc-4-piperidone (3.4g, 17.3mmol) and Na (AcO)3BH (4.0g, 18.8mmol) was reacted at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 5.5g of product in 87% yield. LCMS (ESI) 424(M + Na)+。
Step 10.1- (4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone
In a 100mL round-bottomed flask, tert-butyl 4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate (5.5g, 13.7mmol) was dissolved in CH2Cl2(50mL), trifluoroacetic acid (10mL) was added and the reaction was carried out at room temperature for 1 h. After completion of the reaction, the solvent and trifluoroacetic acid were removed by distillation under reduced pressure. The remainder being dissolved in CH2Cl2(50mL), Ac was added sequentially2O (2.8g, 27.4mmol) and Et3N (6mL), at room temperature for 0.5 h. After the reaction is finished, adding water for dilution, and adding CH2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 4.1g of product in 87% yield. LCMS (ESI) 344(M + H) M/z+。
Step 11.1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone
In a 100mL round-bottom flask equipped with a hydrogen balloon, 1- (4- (3- (3- (difluoromethyl) -4-nitro) was placed1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (4.1g, 11.9mmol) was dissolved in MeOH (50mL), Pd/C (10% wet powder, 50 wt% moisture, 2.0g) was added, and the reaction was stirred at room temperature for 2H. After completion of the reaction, filtration was carried out and the filter residue was washed with MeOH. The filtrate was concentrated under reduced pressure to give 3.2g of product, which was used directly in the next reaction. LCMS (ESI) 314(M + H) M/z+。
Step 12N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (96mg, 0.38mmol), diisopropylethylamine (DIEA, 98mg, 0.76mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (HATU, 175mg, 0.46mmol), and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 20: 1), giving 126mg of product in 61% yield. LCMS (ESI) M/z 549(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.47(s,1H),8.49(s,1H),8.10(s,1H),8.07–8.02(m,2H),7.88(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.88(t,J=54.6Hz,1H),6.15(tt,J=55.4,4.2Hz,1H),5.00–4.90(m,1H),4.55(td,J=13.5,4.2Hz,2H),4.28–4.19(m,1H),3.83(t,J=7.6Hz,2H),3.79–3.70(m,1H),3.54–3.48(m,2H),3.21–3.11(m,1H),3.03–2.94(m,1H),2.51–2.42(m,1H),2.09(s,3H),1.78–1.67(m,2H),1.38–1.22(m,2H).
Example 2
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.1- (4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) -2-hydroxyethan-1-one
In a 50mL round-bottomed flask, tert-butyl 4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate (1.0g, 2.5mmol) was dissolved in CH2Cl2(10mL), trifluoroacetic acid (3mL) was added and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent and trifluoroacetic acid were removed by distillation under reduced pressure. The remainder being dissolved in CH2Cl2(10mL), glycolic acid (228mg, 3.0mmol), DIEA (645mg, 5.0mmol) and HATU (1.1g, 3.0mmol) were added in this order and reacted at room temperature for 0.5 h. After the reaction is finished, adding water for dilution, and adding CH2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtration and concentration, the residue was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 700mg of product in 78% yield. LCMS (ESI) 360(M + H) M/z+。
Step 2.1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) -2-hydroxyethan-1-one
In a 25mL round bottom flask equipped with a hydrogen balloon, 1- (4- (3- (3- (difluoromethyl) -4-nitro-1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) -2-hydroxyethan-1-one (700mg, 1.9mmol) was dissolved in MeOH (10mL), Pd/C (10% wet powder, 50 wt% moisture, 300mg) was added, and the reaction was stirred at room temperature for 2H. After completion of the reaction, filtration was carried out and the filter residue was washed with MeOH. The filtrate was concentrated under reduced pressure to yield 580mg of product, which was used directly in the next reaction. LCMS (ESI) 330(M + H) M/z+。
Step 3.6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) -2-hydroxyethan-1-one (125mg, 0.38mmol), 6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (96mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 40: 1), yielding 145mg of product in 68% yield. LCMS (ESI) 565(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.11(s,1H),8.08–8.03(m,2H),7.89(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),6.16(tt,J=55.4,4.3Hz,1H),5.00–4.91(m,1H),4.56(td,J=13.5,4.3Hz,2H),4.20–4.11(m,3H),3.87–3.79(m,2H),3.67(s,1H),3.56–3.45(m,3H),3.25–3.16(m,1H),3.09–2.99(m,1H),2.57–2.48(m,1H),1.81–1.71(m,2H),1.42–1.29(m,2H).
Example 3
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.4-iodo-1- (2,2, 2-trifluoroethyl) -1H-pyrazole
In a 150mL round bottom flask, 4-iodopyrazole (5.0g, 25.7mmol) was dissolved in DMF (50mL) and 2,2, 2-trifluoroethyl trifluoromethanesulfonate was added(6.6g, 28.3mmol) and K2CO3(7.1g, 51.4mmol) and then heated to 90 ℃ for reaction for 3 h. After completion of the reaction, water was added for dilution, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 4.3g of product in 60% yield. LCMS (ESI) M/z 281(M + H)+。
Step 2 methyl 6- (1- (2,2, 2-trifluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate
4-iodo-1- (2,2, 2-trifluoroethyl) -1H-pyrazole (4.3g, 15.4mmol), pinacol diboron (7.8g, 30.8mmol), Pd (dppf) Cl were added to a 100mL round-bottomed flask under nitrogen2(1.1g, 1.5mmol), AcOK (4.5g, 46.2mmol), dioxane (50mL), and the temperature was raised to 100 ℃ for reaction for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, methyl 6-bromo-2-pyridinecarboxylate (3.3g, 15.4mmol), Pd (PPh) were added to a 100mL round-bottom flask under nitrogen protection3)4(1.7g,1.5mmol),Na2CO3(3.3g, 30.8mmol), dioxane (50mL), H2O (10mL), heated to 80 ℃ and reacted for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 3.1g of product in 71% yield. LCMS (ESI) 286(M + H) M/z+。
Step 3.6- (1- (2,2, 2-trifluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
Methyl 6- (1- (2,2, 2-trifluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate (3.1g, 10.8mmol) was dissolved in MeOH (30mL), and a solution of NaOH (1M 30mL) was added to react at room temperature for 1H. After completion of the reaction, MeOH was concentrated, diluted with water, and extracted with EtOAc. Adjusting pH of water phase to 3 with 4M hydrochloric acid, precipitating solid, filtering, and adding H2O wash to give 2.5g of product as a solid in 85% yield. LCMS (ESI) M/z 272(M + H)+。
Step 4N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (2,2, 2-trifluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (103mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column chromatography
(CH2Cl2MeOH (v/v) ═ 40: 1), yielding 190mg of product in 88% yield. LCMS (ESI) M/z 567(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.47(s,1H),8.50(s,1H),8.12(s,1H),8.11(s,1H),8.06(d,J=7.5Hz,1H),7.90(t,J=7.8Hz,1H),7.66(d,J=7.8Hz,1H),6.88(t,J=54.6Hz,1H),5.00–4.90(m,1H),4.80(q,J=8.3Hz,2H),4.28–4.19(m,1H),3.83(t,J=7.4Hz,2H),3.79–3.71(m,1H),3.51(t,J=6.5Hz,2H),3.21–3.11(m,1H),3.04–2.94(m,1H),2.52–2.42(m,1H),2.09(s,3H),1.80–1.69(m,2H),1.39–1.22(m,2H).
Example 4
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) -2-hydroxyethan-1-one (125mg, 0.38mmol), 6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (103mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 40: 1), yielding 130mg of product in 59% yield. LCMS (ESI) M/z 583(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.14–8.09(m,2H),8.07(d,J=7.6Hz,1H),7.91(t,J=7.7Hz,1H),7.66(d,J=7.8Hz,1H),6.88(t,J=54.5Hz,1H),5.00–4.90(m,1H),4.80(q,J=8.3Hz,2H),4.19–4.12(m,3H),3.87–3.79(m,2H),3.57–3.44(m,3H),3.25–3.16(m,1H),3.09–2.99(m,1H),2.56–2.48(m,1H),1.80–1.71(m,2H),1.42–1.29(m,2H).
Example 5
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.1- (difluoromethyl) -4-iodo-1H-pyrazole
In a 150mL round-bottomed flask, 4-iodopyrazole (5.0g, 25.7mmol) was dissolvedTo DMF (50mL) was added sodium 2-chloro-2, 2-difluoroacetate (4.3g, 28.3mmol) and K2CO3(7.1g, 51.4mmol) and then heated to 100 ℃ for reaction for 16 h. After completion of the reaction, water was added for dilution, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 2.6g of product in 41% yield. LCMS (ESI) M/z 245(M + H)+。
Step 2 methyl 6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate
1- (difluoromethyl) -4-iodo-1H-pyrazole (2.6g, 10.6mmol), pinacol diboron diboride (5.4g, 21.2mmol), Pd (dppf) Cl was added to a 100mL round bottom flask under nitrogen2(732mg, 1.0mmol), AcOK (3.1g, 31.8mmol), dioxane (40mL), and heated to 100 ℃ for reaction for 6 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, methyl 6-bromo-2-pyridinecarboxylate (2.3g, 10.6mmol), Pd (PPh) were added to a 100mL round-bottom flask under nitrogen protection3)4(1.1g,1.0mmol),Na2CO3(2.2g, 21.2mmol), dioxane (40mL), H2O (mL) was warmed to 80 ℃ for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 1: 1) to give 1.7g of product in 63% yield. LCMS (ESI) 254(M + H) M/z+。
Step 3.6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
Methyl 6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate (1.7g, 6.7mmol) was dissolved in MeOH (20mL), and a solution of NaOH (1M 20mL) was added to react at room temperature for 1H. After completion of the reaction, MeOH was concentrated, diluted with water, and extracted with EtOAc. Adjusting pH of water phase to 3 with 4M hydrochloric acid, precipitating solid, filtering, and adding H2O washing to obtain 1.1g of solid product with the yield of 69%. LCMS (ESI) 240(M + H) M/z+。
Step 4.N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (91mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 40: 1), yielding 117mg of product in 58% yield. LCMS (ESI) 535(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.50(s,1H),8.38(s,1H),8.22(s,1H),8.11(d,J=7.5Hz,1H),7.94(t,J=7.8Hz,1H),7.70(d,J=7.8Hz,1H),7.27(d,J=60.3Hz,1H),6.89(t,J=54.6Hz,1H),5.01–4.90(m,1H),4.29–4.19(m,1H),3.83(t,J=7.5Hz,2H),3.79–3.70(m,1H),3.52(t,J=6.6Hz,2H),3.21–3.12(m,1H),3.05–2.95(m,1H),2.52–2.43(m,1H),2.10(s,3H),1.81–1.68(m,2H),1.39–1.22(m,2H).
Example 6
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-methyl-1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 499(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.49(s,1H),8.50(s,1H),8.05–7.99(m,2H),7.96(s,1H),7.86(t,J=7.8Hz,1H),7.62(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),5.00–4.91(m,1H),4.29–4.20(m,1H),4.00(s,3H),3.83(t,J=7.6Hz,2H),3.79–3.71(m,1H),3.56–3.48(m,2H),3.21–3.11(m,1H),3.04–2.94(m,1H),2.51–2.43(m,1H),2.10(s,3H),1.77–1.67(m,2H),1.39–1.23(m,2H).
Example 7
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-ethyl-1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 513(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.52(s,1H),8.50(s,1H),8.08–7.97(m,3H),7.86(t,J=7.7Hz,1H),7.63(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),5.00–4.89(m,1H),4.33–4.18(m,3H),3.83(t,J=7.5Hz,2H),3.79–3.70(m,1H),3.57–3.46(m,2H),3.22–3.11(m,1H),3.04–2.93(m,1H),2.52–2.41(m,1H),2.10(s,3H),1.75–1.68(m,2H),1.58(t,J=7.4Hz,3H),1.40–1.22(m,2H).
Example 8
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-isopropyl-1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 527(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.56(s,1H),8.51(s,1H),8.08(s,1H),8.03(s,1H),8.00(d,J=7.8Hz,1H),7.86(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),5.04–4.89(m,1H),4.68–4.51(m,1H),4.31–4.18(m,1H),3.84(t,J=7.5Hz,2H),3.79–3.71(m,1H),3.56–3.47(m,2H),3.21–3.12(m,1H),3.04–2.94(m,1H),2.52–2.42(m,1H),2.10(s,3H),1.82–1.72(m,2H),1.60(d,J=6.7Hz,6H),1.39–1.23(m,2H).
Example 9
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.2- (4-iodo-1H-pyrazol-1-yl) acetonitrile
In a 250mL round bottom flask, 4-iodopyrazole (10.0g, 51.5mmol) was dissolved in DMF (100mL), bromoacetonitrile (6.8g, 56.6mmol) and K were added2CO3(14g, 103.0mmol) and then heated to 50 ℃ for reaction for 3 h. After completion of the reaction, water was added for dilution, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 5: 1) to give 11.2g of product in 93% yield. LCMS (ESI) 234(M + H) M/z+。
Step 2.1- (4-iodo-1H-pyrazol-1-yl) cyclopropane-1-carbonitrile
DMSO (50mL) was added to a 150mL round bottom flask and placed in an ice water bath to cool. NaH (3.4g, 85.6mmol, 60%) was then added and the reaction stirred for 20 min. To the above reaction solution were added dropwise 2- (4-iodo-1H-pyrazol-1-yl) acetonitrile (5.0g, 21.4mmol) and 1, 2-dibromoethane (12.1g, 64.2mmol)mmol) of DMSO (10mL) and naturally warmed to room temperature for 8 h. After the reaction was completed, the upper reaction solution was poured into saturated NH of ice4Aqueous Cl, aqueous phase extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 10: 1) to give 1.8g of product in 32% yield. LCMS (ESI) 260(M + H) M/z+。
Step 3.6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
1- (4-iodo-1H-pyrazol-1-yl) cyclopropane-1-carbonitrile (1.8g, 6.9mmol), pinacol diboron diboride (3.5g, 13.8mmol), Pd (dppf) Cl were added to a 100mL round-bottomed flask under nitrogen protection2(0.5g, 0.7mmol), AcOK (2.0g, 20.7mmol), and DMF (30mL) were reacted at 100 ℃ for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, 6-bromo-2-pyridinecarboxylic acid (1.4g, 6.9mmol), Pd (PPh) were added to a 100mL round-bottomed flask under nitrogen protection3)4(0.8g,0.7mmol),Na2CO3(2.2g, 20.7mmol), dioxane (40mL), H2O (10mL) was warmed to 80 ℃ and reacted for 10 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc. The aqueous phase was adjusted to pH 1 with 1M HCl, extracted with EtOAc, washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave 830mg of product in 47% yield. LCMS (ESI) M/z 255(M + H)+。
Step 4.N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (97mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 40: 1), yielding 175mg of product in 84% yield. LCMS (ESI) 550(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.46(s,1H),8.49(s,1H),8.19(s,1H),8.10–8.05(m,2H),7.91(t,J=7.7Hz,1H),7.64(dd,J=7.9,1.1Hz,1H),6.90(t,J=54.6Hz,1H),5.01–4.91(m,1H),4.29–4.20(m,1H),3.84(t,J=7.5Hz,2H),3.80–3.71(m,1H),3.52(t,J=7.1Hz,2H),3.21–3.11(m,1H),3.04–2.94(m,1H),2.53–2.43(m,1H),2.10(s,3H),1.93–1.87(m,4H),1.80–1.69(m,2H),1.39–1.23(m,2H).
Example 10
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 9. LCMS (ESI) M/z 564(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.50(s,1H),8.49(s,1H),8.26(s,1H),8.16(s,1H),8.06(dd,J=7.5,1.0Hz,1H),7.90(t,J=7.8Hz,1H),7.66(dd,J=7.9,1.1Hz,1H),6.88(t,J=54.6Hz,1H),5.01–4.91(m,1H),4.29–4.20(m,1H),3.84(t,J=7.5Hz,2H),3.80–3.71(m,1H),3.56–3.49(m,2H),3.20–3.05(m,3H),3.03–2.93(m,3H),2.53–2.43(m,1H),2.43–2.30(m,1H),2.27–2.15(m,1H),2.09(s,3H),1.82–1.64(m,2H),1.31(m,2H).
Example 11
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (aminomethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide (150mg, 0.27mmol) was dissolved in MeOH (10mL) and placed in an ice-water bath to cool. Adding anhydrous CoCl into the solution2(0.4mg, 0.003mmol) and NaBH4(12mg, 0.32mmol), reaction for 20min at constant temperature, after completion of the reaction, dilution with water, extraction with EtOAc, combination of organic phases, washing with saturated NaCl solution, anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 20: 1), yielding 120mg of product in 79% yield. LCMS (ESI) 568(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.56(s,1H),8.49(s,1H),8.12(s,1H),8.06(s,1H),8.00(dd,J=7.6,0.8Hz,1H),7.86(t,J=7.8Hz,1H),7.63(dd,J=7.8,0.7Hz,1H),6.87(t,J=54.6Hz,1H),5.01–4.87(m,1H),4.29–4.15(m,1H),3.82(t,J=7.5Hz,2H),3.78–3.69(m,1H),3.50(t,J=6.4Hz,2H),3.21(s,2H),3.19–3.11(m,1H),3.02–2.92(m,1H),2.69–2.56(m,2H),2.51–2.31(m,3H),2.09(s,3H),2.07–1.91(m,2H),1.78–1.68(m,2H),1.38–1.20(m,2H).
Example 12
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanenitrile
DMSO (50mL) was added to a 150mL round bottom flask and placed in an ice water bath to cool. NaH (3.4g, 85.6mmol, 60%) was then added and the reaction stirred for 20 min. To the reaction mixture, a mixture of 2- (4-iodo-1H-pyrazol-1-yl) acetonitrile (5.0g, 21.4mmol) and methyl iodide (9.1g, 64.2mmol) in DMSO (10mL) was added dropwise, and the mixture was allowed to spontaneously warm to room temperature for reaction for 8 hours. After the reaction was completed, the upper reaction solution was poured into saturated NH of ice4Aqueous Cl, aqueous phase extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 5: 1) to give 4.2g of product in 75% yield. LCMS (ESI) 262(M + H) M/z+。
Step 2.6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
In a 100mL round-bottom flask, under nitrogen protection, 2- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanenitrile (2.0g, 7.7mmol), pinacol diboron diboride (3.9g, 15.4mmol), Pd (dppf) Cl2(0.5g, 0.7mmol), AcOK (2.3g, 23.1mmol), and DMF (30mL) were reacted at 100 ℃ for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, 6-bromo-2-pyridinecarboxylic acid (1.5g, 7.7mmol), Pd (PPh) was added to a 100mL round-bottomed flask under nitrogen protection3)4(0.8g,0.7mmol),Na2CO3(2.4g, 23.1mmol), dioxane (40mL), H2O (10mL) was warmed to 80 ℃ and reacted for 10 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc. The aqueous phase was adjusted to pH 1 with 1M HCl, extracted with EtOAc, washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave 1.6g of product, 81% yield. LCMS (ESI) M/z 257(M + H)+。
Step 3N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (97mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 40: 1), giving 132mg of product in 63% yield. LCMS (ESI) M/z 552(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.52(s,1H),8.49(s,1H),8.29(s,1H),8.13(s,1H),8.05(dd,J=7.5,1.1Hz,1H),7.90(t,J=7.8Hz,1H),7.66(dd,J=7.9,1.1Hz,1H),6.88(t,J=54.6Hz,1H),5.00–4.90(m,1H),4.28–4.19(m,1H),3.83(t,J=7.5Hz,2H),3.79–3.70(m,1H),3.55–3.48(m,2H),3.21–3.11(m,1H),3.04–2.94(m,1H),2.51–2.42(m,1H),2.09(s,3H),2.08(s,6H),1.81–1.67(m,2H),1.41–1.22(m,2H).
Example 13
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was reduced from example 12 with reference to the procedure of example 11. LCMS (ESI) 556(M + H) M/z ═ M/z+。1HNMR(400MHz,Chloroform-d)δ10.57(s,1H),8.49(s,1H),8.20(s,1H),8.06(s,1H),7.99(d,J=7.4Hz,1H),7.86(t,J=7.8Hz,1H),7.63(d,J=7.9Hz,1H),6.88(t,J=54.6Hz,1H),4.99–4.90(m,1H),4.28–4.19(m,1H),3.83(t,J=7.6Hz,2H),3.78–3.70(m,1H),3.55–3.47(m,2H),3.20–3.11(m,1H),3.08(s,2H),3.03–2.93(m,1H),2.51–2.42(m,1H),2.09(s,3H),1.81–1.68(m,2H),1.63(s,6H),1.39–1.21(m,2H).
Example 14
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (hydroxymethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1. Ethyl 2- (4-iodo-1H-pyrazol-1-yl) acetate
In a 250mL round bottom flask, 4-iodopyrazole (10.0g, 51.5mmol) was dissolved in DMF (100mL), ethyl bromoacetate (9.4g, 56.6mmol) and K were added2CO3(14.0g, 103.0mmol) and then heated to 50 ℃ for reaction for 3 h. After completion of the reaction, water was added for dilution, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 5: 1) to give 11.6g of product in 80% yield. LCMS (ESI) M/z 281(M + H)+。
Step 2 Ethyl 1- (4-iodo-1H-pyrazol-1-yl) cyclobutane-1-carboxylate
DMSO (50mL) was added to a 150mL round bottom flask and placed in an ice water bath to cool. NaH (2.8g, 71.4mmol, 60%) was then added and the reaction stirred for 20 min. To the above reaction solution were added dropwise ethyl 2- (4-iodo-1H-pyrazol-1-yl) acetate (5.0g, 17.8mmol) and 1A mixture of 3-dibromopropane (10.8g, 53.4mmol) in DMSO (10mL) was allowed to spontaneously warm to room temperature for 8 hours. After the reaction was completed, the upper reaction solution was poured into saturated NH of ice4Aqueous Cl, aqueous phase extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 5: 1) to give 3.6g of product in 63% yield. LCMS (ESI) 321(M + H) M/z+。
Step 3.(1- (4-iodo-1H-pyrazol-1-yl) cyclobutyl) methanol
Ethyl 1- (1- (tert-butylcarbonyl) azetidin-3-yl) -4-nitro-1H-pyrazole-3-carboxylate (3.6g, 11.2mmol) in a 250mL three-necked round-bottomed flask equipped with a thermometer under nitrogen2Cl2(50mL) and cooled in a salt-ice bath. Slowly dripping 1M DIBAL-H n-hexane solution (33mL) into the upper solution while maintaining the internal temperature below-10 deg.C, and pouring saturated NH into the upper reaction solution4Cl solution (100mL), filtered after stirring, the filtrate was extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 1.7g of product in 54% yield. LCMS (ESI) M/z 279(M + H)+。
Step 4 methyl 6- (1- (1- (hydroxymethyl) cyclobutane) -1H-pyrazol-4-yl) -2-pyridinecarboxylate
In a 100mL round-bottom flask, under nitrogen, was added (1- (4-iodo-1H-pyrazol-1-yl) cyclobutyl) methanol (1.7g, 6.1mmol), pinacol ester of diboronic acid (3.1g, 12.2mmol), Pd (dppf) Cl2(439mg, 0.6mmol), AcOK (1.8g, 18.3mmol), and DMF (20mL) were heated to 100 ℃ and reacted for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O,Extraction with EtOAc, combining the organic phases, washing with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, methyl 6-bromo-2-pyridinecarboxylate (1.3g, 6.1mmol), Pd (PPh) were added to a 100mL round-bottom flask under nitrogen protection3)4(693mg,0.6mmol),Na2CO3(1.3g, 12.2mmol), dioxane (20mL), H2O (5mL) was warmed to 80 ℃ and reacted for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 2: 1) to give 1.2g of product in 68% yield. LCMS (ESI) 288(M + H)+。
Step 5.6- (1- (1- (hydroxymethyl) cyclobutane) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
Methyl 6- (1- (1- (hydroxymethyl) cyclobutane) -1H-pyrazol-4-yl) -2-pyridinecarboxylate (1.2g, 4.2mmol) was dissolved in MeOH (20mL), and NaOH (1M 20mL) was added to react at room temperature for 1H. After completion of the reaction, MeOH was concentrated, diluted with water, and extracted with EtOAc. Adjusting pH of water phase to 3 with 4M hydrochloric acid, precipitating solid, filtering, and adding H2O washing to obtain 1.0g of solid product with the yield of 87%. LCMS (ESI) M/z 274(M + H)+。
Step 6N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (hydroxymethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (1- (hydroxymethyl) -1H-pyrazol-1-yl) was added) Cyclobutane) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (104mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 20: 1), yielding 110mg of product in 51% yield. LCMS (ESI) M/z 569(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.51(s,1H),8.51(s,1H),8.09(s,1H),8.07–8.00(m,2H),7.92–7.84(m,1H),7.67–7.61(m,1H),6.89(t,J=54.6Hz,1H),5.20–5.06(m,1H),5.03–4.91(m,1H),4.43–4.16(m,2H),4.04(s,2H),3.90–3.81(m,2H),3.80–3.69(m,1H),3.61–3.44(m,2H),3.26–3.10(m,1H),3.04–2.91(m,1H),2.85–2.41(m,4H),2.11(s,3H),2.06–1.95(m,1H),1.83–1.67(m,2H),1.39–1.30(m,2H).
Example 15
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridineamide
Step 1.1- (4-iodo-1H-pyrazol-1-yl) -2-methylpropan-2-ol
In a 150mL round bottom flask, 4-iodopyrazole (5.0g, 25.7mmol) was dissolved in DMF (50mL) and 1-chloro-2-methyl-2-propanol (3.1g, 28.3mmol) and K were added3PO4(10.9g, 51.4mmol) and then heated to 50 ℃ for 10 h. After completion of the reaction, water was added for dilution, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated NaCl solution and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 4.2g of product in 58% yield. LCMS (ESI) M/z 281(M + H)+。
Step 2 methyl 6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate
1- (4-iodo-1H-pyrazol-1-yl) -2-methylpropan-2-ol (4.2g, 15.0mmol), pinacol diboron diboride (7.6g, 30.0mmol), Pd (dppf) Cl were added to a 100mL round bottom flask under nitrogen protection2(1.1g, 1.5mmol), AcOK (4.4g, 45mmol), DMF (50mL), and heated to 100 ℃ for reaction for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtering and concentrating, and directly reacting the obtained residue.
The residue obtained above, methyl 6-bromo-2-pyridinecarboxylate (3.2g, 15.0mmol), Pd (PPh) were added to a 100mL round-bottomed flask under nitrogen protection3)4(1.7g,1.5mmol),Na2CO3(3.2g, 30.0mmol), dioxane (50mL), H2O (10mL) was warmed to 80 ℃ and reacted for 2 h. After completion of the reaction, it was filtered and the filter residue was washed with EtOAc. Adding H into the filtrate2O, extracted with EtOAc, the organic phases were combined, washed with saturated NaCl solution, anhydrous Na2SO4Drying, filtration and concentration gave a residue which was purified by column chromatography on silica gel (PE: EtOAc (v/v) ═ 3: 1) to give 3.0g of product in 73% yield. LCMS (ESI) M/z 276(M + H)+。
Step 3.6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid
Methyl 6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylate (3.0g, 10.9mmol) was dissolved in MeOH (30mL), and a solution of NaOH (1M 30mL) was added to react at room temperature for 1H. After completion of the reaction, MeOH was concentrated, diluted with water, and extracted with EtOAc. Adjusting pH of water phase to 3 with 4M hydrochloric acid, precipitating solid, filtering, and adding H2O washing to obtain 2.5g of solid product with the yield of 88%. LCMS (ESI) with m/z being 262: (M+H)+。
Step 4.N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridineamide
In a 25mL round bottom flask, 1- (4- (3- (4-amino-3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidin-1-yl) ethanone (120mg, 0.38mmol), 6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridinecarboxylic acid (99mg, 0.38mmol), DIEA (98mg, 0.76mmol), HATU (175mg, 0.46mmol) and CH were added2Cl2(5mL), the reaction was stirred at room temperature for 1 h. After the reaction is completed, water is added for dilution, and CH is added2Cl2Extracting, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, filtering, concentrating, purifying the residue with silica gel column Chromatography (CH)2Cl2MeOH (v/v) ═ 20: 1), yielding 160mg of product in 76% yield. LCMS (ESI) M/z 557(M + H)+。
1H NMR(400MHz,Chloroform-d)δ10.49(s,1H),8.50(s,1H),8.08(s,1H),8.05–8.00(m,2H),7.88(t,J=7.8Hz,1H),7.64(dd,J=8.1,1.1Hz,1H),6.88(t,J=54.7Hz,1H),5.00–4.90(m,1H),4.28–4.19(m,1H),4.16(s,2H),3.83(t,J=7.5Hz,2H),3.75(d,J=13.6Hz,1H),3.62(s,1H),3.55–3.47(m,2H),3.21–3.11(m,1H),3.03–2.94(m,1H),2.52–2.42(m,1H),2.09(s,3H),1.80–1.72(m,2H),1.41–1.26(m,2H),1.24(s,6H).
Example 16
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-hydroxy-2-methylpropyl-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the procedure of example 14. LCMS (ESI) M/z 557(M + H)+。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.51(s,1H),8.49(s,1H),8.16(s,1H),8.06–7.94(m,2H),7.89(dd,J=7.2,1.3Hz,1H),7.27(t,J=54.2Hz,1H),5.14–5.04(m,1H),5.00(t,J=5.7Hz,1H),4.04–3.94(m,1H),3.75–3.64(m,3H),3.62(d,J=5.6Hz,2H),3.45–3.36(m,2H),3.17–3.06(m,1H),2.95–2.84(m,1H),2.45–2.36(m,1H),1.98(s,3H),1.74–1.59(m,2H),1.54(s,6H),1.26–1.12(m,1H),1.11–1.00(m,1H).
Example 17
6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 13. LCMS (ESI) M/z 585(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.50(s,1H),8.21(s,1H),8.07(s,1H),8.00(d,J=7.7Hz,1H),7.86(t,J=7.7Hz,1H),7.64(d,J=8.0Hz,1H),6.89(t,J=54.6Hz,1H),5.00–4.91(m,1H),3.83(t,J=7.7Hz,2H),3.64–3.56(m,2H),3.51(t,J=7.6Hz,2H),3.09(s,2H),2.90–2.79(m,8H),2.42–2.33(m,1H),1.79–1.71(m,2H),1.65(s,6H),1.39–1.24(m,2H).
Example 18
Methyl 4- (3- (4- (6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
This example was prepared according to the method of example 13. LCMS (ESI) M/z 572(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.58(s,1H),8.50(s,1H),8.21(s,1H),8.07(s,1H),8.00(d,J=7.5Hz,1H),7.86(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.88(t,J=54.6Hz,1H),5.00–4.91(m,1H),4.05–3.89(m,2H),3.87–3.79(m,2H),3.70(s,3H),3.53–3.46(m,2H),3.09(s,2H),3.04–2.95(m,2H),2.44–2.35(m,1H),1.76–1.67(m,2H),1.65(s,6H),1.35–1.21(m,2H).
Example 19
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 485(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.52(s,1H),8.51(s,1H),8.19(s,2H),8.05(d,J=7.7Hz,1H),7.89(t,J=7.8Hz,1H),7.69(d,J=7.9Hz,1H),6.89(t,J=54.6Hz,1H),5.01–4.91(m,1H),4.29–4.21(m,1H),3.84(t,J=7.6Hz,2H),3.80–3.71(m,1H),3.52(t,J=7.3Hz,2H),3.21–3.12(m,1H),3.04–2.94(m,1H),2.52–2.43(m,1H),2.11(s,3H),1.82–1.68(m,2H),1.39–1.23(m,2H).
Example 20
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 514(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.51(s,1H),8.51(s,1H),8.18(s,2H),8.04(d,J=7.8Hz,1H),7.89(t,J=7.8Hz,1H),7.68(d,J=8.0Hz,1H),6.90(t,J=54.6Hz,1H),5.01–4.92(m,1H),3.84(t,J=7.8Hz,2H),3.65–3.58(m,2H),3.52(t,J=7.6Hz,2H),2.90–2.79(m,8H),2.44–2.34(m,1H),1.80–1.71(m,2H),1.40–1.25(m,2H).
Example 21
Methyl 4- (3- (4- (6- (1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
This example was prepared according to the method of example 5. LCMS (ESI) 501(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.51(s,1H),8.51(s,1H),8.19(s,2H),8.05(d,J=7.5Hz,1H),7.89(t,J=7.7Hz,1H),7.69(d,J=7.9Hz,1H),6.89(t,J=54.7Hz,1H),5.01–4.91(m,1H),4.07–3.91(m,2H),3.84(t,J=7.6Hz,2H),3.70(s,3H),3.51(d,J=7.6Hz,2H),3.04–2.94(m,2H),2.47–2.36(m,1H),1.79–1.67(m,2H),1.35–1.21(m,2H).
Example 22
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 497(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.51(s,1H),8.51(s,1H),8.18(s,2H),8.04(d,J=7.6Hz,1H),7.89(t,J=7.7Hz,1H),7.68(d,J=7.7Hz,1H),6.89(t,J=54.5Hz,1H),6.59(dd,J=16.8,10.6Hz,1H),6.27(dd,J=16.8,1.9Hz,1H),5.69(dd,J=10.7,1.9Hz,1H),5.01–4.91(m,1H),4.34–4.21(m,1H),3.96–3.77(m,3H),3.58–3.49(m,2H),3.29–2.94(m,2H),2.56–2.43(m,1H),1.83–1.68(m,2H),1.44–1.22(m,2H).
Example 23
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 497(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(d,J=7.8Hz,1H),8.11(d,J=7.8Hz,1H),7.97(t,J=7.8Hz,1H),7.71(d,J=2.2Hz,1H),7.03–7.01(m,1H),6.90(t,J=54.7Hz,1H),6.59(dd,J=16.9,10.6Hz,1H),6.27(dd,J=16.8,2.0Hz,1H),5.68(dd,J=10.6,1.9Hz,1H),5.04–4.90(m,1H),4.35–4.20(m,1H),3.96–3.77(m,3H),3.54(t,J=7.3Hz,2H),3.30–3.02(m,2H),2.58–2.44(m,1H),1.85–1.70(m,2H),1.43–1.29(m,2H).
Example 24
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 485(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(d,J=7.7Hz,1H),8.11(d,J=7.9Hz,1H),7.97(t,J=7.8Hz,1H),7.71(d,J=2.3Hz,1H),7.05–7.00(m,1H),6.83(d,J=54.6Hz,1H),5.03–4.90(m,1H),4.35–4.19(m,1H),3.85(t,J=7.4Hz,2H),3.80–3.71(m,1H),3.53(t,J=7.2Hz,2H),3.24–3.10(m,1H),3.06–2.93(m,1H),2.56–2.41(m,1H),2.11(s,3H),1.83–1.69(m,2H),1.40–1.29(m,2H).
Example 25
Methyl 4- (3- (4- (6- (1H-pyrazol-3-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
This example was prepared according to the method of example 5. LCMS (ESI) 501(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.50(s,1H),8.55(s,1H),8.21(d,J=7.8Hz,1H),8.16(d,J=7.9Hz,1H),8.01(t,J=7.8Hz,1H),7.76(d,J=2.3Hz,1H),7.07(d,J=2.3Hz,1H),6.88(t,J=54.8Hz,1H),5.12–4.96(m,1H),4.17–3.99(m,2H),3.94(t,J=7.5Hz,2H),3.76(s,3H),3.60(t,J=7.5Hz,2H),3.12–2.97(m,2H),2.57–2.42(m,1H),1.87–1.71(m,2H),1.43–1.32(m,2H).
Example 26
N- (3- (difluoromethyl) -1- (1- (1-propionylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 499(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.50(s,1H),8.16(d,J=7.5Hz,1H),8.11(d,J=8.0Hz,1H),7.96(t,J=7.8Hz,1H),7.71(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.6Hz,1H),5.10–4.91(m,1H),4.42–4.25(m,1H),4.02–3.87(m,2H),3.87–3.76(m,1H),3.68–3.50(m,2H),3.19–2.89(m,2H),2.65–2.45(m,1H),2.36(q,J=7.5Hz,2H),1.84–1.71(m,2H),1.42–1.30(m,2H),1.16(t,J=7.4Hz,3H).
Example 27
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 501(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(d,J=7.6Hz,1H),8.11(d,J=8.0Hz,1H),7.97(t,J=7.8Hz,1H),7.71(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.6Hz,1H),5.08–4.91(m,1H),4.27–4.09(m,3H),3.98–3.79(m,2H),3.66–3.44(m,3H),3.27–2.94(m,2H),2.67–2.47(m,1H),1.87–1.68(m,2H),1.48–1.33(m,2H).
Example 28
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 514(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.46(s,1H),8.50(s,1H),8.15(d,J=7.8Hz,1H),8.11(d,J=7.8Hz,1H),7.96(t,J=7.8Hz,1H),7.71(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.7Hz,1H),5.04–4.94(m,1H),3.89(t,J=7.4Hz,2H),3.66–3.59(m,2H),3.55(t,J=7.5Hz,2H),2.89–2.78(m,8H),2.47–2.38(m,1H),1.81–1.72(m,2H),1.42–1.29(m,2H).
Example 29
N- (3- (difluoromethyl) -1- (1- (1-isobutyrylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 513(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.50(s,1H),8.18–8.07(m,2H),7.96(t,J=7.8Hz,1H),7.71(d,J=2.3Hz,1H),7.05–6.74(m,2H),5.06–4.89(m,1H),4.41–4.26(m,1H),3.96–3.77(m,3H),3.63–3.48(m,2H),3.25–3.07(m,1H),3.02–2.89(m,1H),2.87–2.74(m,1H),2.60–2.45(m,1H),1.86–1.66(m,2H),1.44–1.20(m,2H),1.13(d,J=6.8Hz,6H).
Example 30
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 4. LCMS (ESI) M/z 597(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.13(s,1H),8.12(s,1H),8.07(d,J=7.7Hz,1H),7.91(t,J=7.8Hz,1H),7.67(d,J=8.1Hz,1H),6.89(t,J=54.6Hz,1H),5.01–4.91(m,1H),4.81(q,J=8.3Hz,2H),4.51–4.42(m,1H),4.26–4.12(m,1H),3.94–3.81(m,3H),3.72–3.63(m,1H),3.59–3.49(m,2H),3.23–3.09(m,2H),2.59–2.48(m,1H),1.84–1.72(m,2H),1.44–1.35(m,2H),1.33(d,J=6.6Hz,3H).
Example 31
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 4. LCMS (ESI) M/z 597(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.12(s,1H),8.11(s,1H),8.07(d,J=7.5Hz,1H),7.91(t,J=7.8Hz,1H),7.66(d,J=7.9Hz,1H),6.88(t,J=54.6Hz,1H),5.01–4.89(m,1H),4.80(q,J=8.3Hz,2H),4.52–4.41(m,1H),4.25–4.11(m,1H),3.90(s,1H),3.84(t,J=7.4Hz,2H),3.71–3.61(m,1H),3.58–3.47(m,2H),3.25–3.08(m,2H),2.59–2.46(m,1H),1.85–1.72(m,2H),1.44–1.35(m,2H),1.32(d,J=6.5Hz,3H).
Example 32
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 4. LCMS (ESI) M/z 611(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.12(s,1H),8.12(s,1H),8.07(d,J=7.6Hz,1H),7.91(t,J=7.8Hz,1H),7.66(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),5.01–4.91(m,1H),4.80(q,J=8.4Hz,2H),4.61(s,1H),4.23–4.07(m,2H),3.84(t,J=7.8Hz,2H),3.53(t,J=7.5Hz,2H),3.26–3.13(m,2H),2.57–2.48(m,1H),1.82–1.74(m,2H),1.50(s,6H),1.37(s,2H).
Example 33
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 4. LCMS (ESI) M/z 603(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.52(s,1H),8.13(s,1H),8.11(s,1H),8.06(d,J=7.8Hz,1H),7.91(t,J=7.8Hz,1H),7.66(d,J=7.9Hz,1H),6.88(t,J=54.6Hz,1H),4.99–4.89(m,1H),4.80(q,J=8.3Hz,2H),3.81(t,J=7.7Hz,2H),3.59–3.46(m,4H),3.08–2.98(m,2H),2.82(s,3H),2.48–2.40(m,1H),1.88–1.77(m,2H),1.58–1.46(m,2H).
Example 34
(S) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the procedure of example 2, step 3. LCMS (ESI) M/z 579(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.11(s,1H),8.08–8.02(m,2H),7.89(t,J=7.8Hz,1H),7.64(d,J=7.9Hz,1H),6.89(t,J=54.7Hz,1H),6.16(tt,J=55.4,4.3Hz,1H),5.01–4.90(m,1H),4.56(td,J=13.5,4.2Hz,2H),4.50–4.41(m,1H),4.25–4.10(m,1H),3.90(s,1H),3.83(t,J=7.4Hz,2H),3.72–3.61(m,1H),3.59–3.47(m,2H),3.25–3.08(m,2H),2.59–2.47(m,1H),1.84–1.71(m,2H),1.43–1.34(m,2H),1.32(d,J=6.4Hz,3H).
Example 35
(R) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the procedure of example 2, step 3. LCMS (ESI) M/z 579(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.50(s,1H),8.11(s,1H),8.08–8.02(m,2H),7.89(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),6.16(tt,J=55.3,4.2Hz,1H),5.01–4.91(m,1H),4.56(td,J=13.5,4.3Hz,2H),4.46(q,J=6.5Hz,1H),4.24–4.11(m,1H),3.84(t,J=7.4Hz,2H),3.72–3.61(m,1H),3.57–3.48(m,2H),3.23–3.08(m,2H),2.58–2.48(m,1H),1.83–1.70(m,2H),1.44–1.34(m,2H),1.32(d,J=6.5Hz,3H).
Example 36
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the procedure of example 2, step 3. LCMS (ESI) M/z 593(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.49(s,1H),8.51(s,1H),8.11(s,1H),8.08–8.02(m,2H),7.89(t,J=7.8Hz,1H),7.65(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),6.16(tt,J=55.3,4.2Hz,1H),5.02–4.90(m,1H),4.67–4.50(m,3H),4.23–4.07(m,2H),3.84(t,J=7.7Hz,2H),3.54(t,J=7.5Hz,2H),3.25–3.14(m,2H),2.57–2.49(m,1H),1.82–1.74(m,2H),1.50(s,6H),1.42–1.30(m,2H).
Example 37
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 33. LCMS (ESI) M/z 585(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.48(s,1H),8.52(s,1H),8.11(s,1H),8.06(s,1H),8.04(d,J=7.6Hz,1H),7.89(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),6.16(tt,J=55.3,4.2Hz,1H),5.03–4.89(m,1H),4.56(td,J=13.5,4.3Hz,2H),3.85(t,J=7.4Hz,2H),3.61–3.48(m,4H),3.10–2.97(m,2H),2.82(s,3H),2.54–2.43(m,1H),1.88–1.78(m,2H),1.59–1.47(m,2H).
Example 38
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the methods of example 17, steps 1 and 2, and example 2, step 3. LCMS (ESI) M/z 578(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.47(s,1H),8.49(s,1H),8.10(s,1H),8.07–8.02(m,2H),7.89(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),6.89(t,J=54.6Hz,1H),6.16(tt,J=55.3,4.2Hz,1H),5.01–4.92(m,1H),4.55(td,J=13.5,4.3Hz,2H),3.85(t,J=7.6Hz,2H),3.64–3.56(m,2H),3.53(t,J=7.4Hz,2H),2.90–2.75(m,8H),2.45–2.33(m,1H),1.81–1.69(m,2H),1.42–1.26(m,2H).
Example 39
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was made according to the method of example 5And (4) preparing. LCMS (ESI) M/z 515(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(d,J=7.7Hz,1H),8.11(d,J=7.8Hz,1H),7.96(t,J=7.8Hz,1H),7.70(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.7Hz,1H),5.01–4.90(m,1H),4.52–4.41(m,1H),4.24–4.11(m,1H),3.93(s,1H),3.84(t,J=7.5Hz,2H),3.72–3.60(m,1H),3.58–3.47(m,2H),3.24–3.08(m,2H),2.59–2.46(m,1H),1.84–1.71(m,2H),1.43–1.28(m,5H).
Example 40
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 515(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(d,J=7.8Hz,1H),8.11(d,J=7.8Hz,1H),7.96(t,J=7.8Hz,1H),7.70(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.7Hz,1H),5.03–4.89(m,1H),4.54–4.41(m,1H),4.27–4.09(m,1H),3.94(s,1H),3.84(t,J=7.4Hz,2H),3.72–3.61(m,1H),3.59–3.47(m,2H),3.26–3.08(m,2H),2.59–2.46(m,1H),1.87–1.71(m,2H),1.44–1.27(m,5H).
EXAMPLE 41
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) M/z 529(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.51(s,1H),8.16(dd,J=7.6,1.1Hz,1H),8.11(d,J=7.9Hz,1H),7.96(t,J=7.7Hz,1H),7.70(d,J=2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.90(t,J=54.7Hz,1H),5.01–4.91(m,1H),4.63(s,1H),4.27–4.04(m,2H),3.84(t,J=7.8Hz,2H),3.54(t,J=7.6Hz,2H),3.28–3.11(m,2H),2.58–2.47(m,1H),1.83–1.73(m,2H),1.50(s,6H),1.42–1.29(m,2H).
Example 42
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
This example was prepared according to the method of example 5. LCMS (ESI) 521(M + H) M/z+。1H NMR(400MHz,Chloroform-d)δ10.45(s,1H),8.53(s,1H),8.15(d,J=7.6Hz,1H),8.11(d,J=7.8Hz,1H),7.97(t,J=7.8Hz,1H),7.71(d,J=2.4Hz,1H),7.06–6.72(m,2H),5.04–4.90(m,1H),3.83(t,J=7.4Hz,2H),3.60–3.43(m,4H),3.11–2.97(m,2H),2.82(s,3H),2.53–2.40(m,1H),1.89–1.78(m,2H),1.59–1.48(m,2H).
Example 43
6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
This example was prepared according to the method of example 12. LCMS (ESI) 568(M + H)+。1H NMR(400MHz,Chloroform-d)δ10.52(s,1H),8.49(s,1H),8.29(s,1H),8.13(s,1H),8.05(dd,J=7.5,1.1Hz,1H),7.90(t,J=7.8Hz,1H),7.66(dd,J=7.9,1.1Hz,1H),6.88(t,J=54.6Hz,1H),5.08–4.91(m,1H),4.27–4.09(m,3H),3.98–3.79(m,2H),3.66–3.44(m,3H),3.27–2.94(m,2H),2.67–2.47(m,1H),2.08(s,6H),1.87–1.68(m,2H),1.48–1.33(m,2H).
Test example a: assay for IRAK4 kinase activity
Detection of Compounds on IRAK4 kinase at K Using the Mobility Shift Assay (MSA)Inhibitory Activity under mATP (IC)50). IRAK4 Kinase was purchased from Carna corporation (cat # 09-145, batch # 14CBS-0020H), Kinase Substrate 8 was purchased from GL Biochem (cat # 112396, batch # P171207-MJI 112396).
The compounds were prepared in DMSO at 100-fold final reaction concentration, starting at 1 μ M and diluted sequentially at 10 concentrations at 3-fold dilution ratio. Then 0.25. mu.L was transferred to a 384-well reaction plate using Echo 550. Using 1-fold kinase buffer (50mM HEPES, pH 7.5, 0.0015% Brij-35,10mM MgCl)22mM DTT) was added to each well of the compound 10. mu.L of a 2.5-fold final kinase solution, shaken, mixed and incubated at room temperature for 10 minutes. A mixed solution of 25/15-fold final concentration of ATP and a Substrate Kinase Substrate 8 was prepared using 1-fold Kinase buffer, and 15. mu.L of a mixed solution of 25/15-fold final concentration of ATP and Substrate (IRAK4 Kinase final concentration of 1nM, Substrate final concentration of 3. mu.M, ATP final concentration of 15.6. mu.M) was added to each well, followed by reaction at room temperature for 60 minutes after shaking and mixing. The reaction was terminated by adding 30. mu.L of stop solution (100mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3,50mM EDTA). And reading the conversion rate data by using a CaliperEZ Reader II, and converting the conversion rate into inhibition rate data. Calculating IC of half inhibitory concentration by using Logit method according to inhibition rate data of each concentration50(Table 1).
TABLE 1 inhibition of IRAK4 kinase Activity by Compounds of the invention
Test example B: cell viability assay
The compounds of the invention inhibit the cellular activity of IRAK4 and were tested in THP-1 cells the stimulus used in this experiment was LPS, which is a TLR4 agonist, stimulating the secretion of TNF α in THP-1 cells via the TLR-IRAK4 signaling pathway.
Once this signaling pathway is inhibited by IRAK4 inhibitors, the production of TNF α is inhibited the secretion of TNF α in this experiment was tested by ELISA.
Adding to each well of a 96-well plate10000 of THP-1 cells in 150. mu.L of RPMI-1640 medium (Gibco, Cat.: 11875-085) solution, then 25. mu.L of test compound (starting with 10. mu.M, 3-fold dilution, 8 concentrations of RPMI-1640 medium each containing 4% DMSO) solution at 8-fold final concentration was added, mixed well and incubated at 37 ℃ for 30 minutes, 25. mu.L of LPS-containing RPMI-1640 medium solution (final LPS concentration of 1. mu.g/mL, final DMSO concentration of 0.5%) was added to each test well, mixed well and incubated at 37 ℃ for 4.5 hours, the well plate 96 was rotated at 2000rpm for 5 minutes, then 50. mu.L of supernatant was taken, the TNF α content in the supernatant was determined with a human ELISA kit (Life Technologies, Cat.: KHC3011), and IC of the compound was calculated by XL-Fit50Values (table 2).
TABLE 2 Activity of the Compounds of the invention for inhibiting LPS-stimulated TNF α secretion in THP-1 cells
Examples | IC50(nM) | Examples | IC50(nM) |
1 | 29 | 31 | 42 |
2 | 27 | 32 | 52 |
3 | 35 | 34 | 46 |
4 | 33 | 35 | 48 |
12 | 43 | 36 | 50 |
13 | 25 | 40 | 26 |
24 | 20 | 41 | 23 |
27 | 18 | 43 | 42 |
The results in tables 1 and 2 show that the compounds of the present invention are effective in inhibiting the activity of IRAK4 kinase and also in inhibiting LPS-stimulated TNF α secretion in THP-1 cells.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the structure:
wherein the content of the first and second substances,
het ring is a five or six membered heteroaromatic ring;
R1selected from: h, D;
R2and R3Each selected from: h, D, alkyl, halogen, OR ORa;
R4Selected from: COR (continuous operating reference)d,CONRbRc,CO2Rd,SO2RdOr SO2NRbRc;
R5Selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRcAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with 1-3R5aSubstitution;
R5aselected from: h, D, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc(ii) a Wherein said alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1-3R5bSubstitution;
R5bselected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc;
Ra,Rb,RcAnd RdEach selected from: h, D, alkyl, alkenyl, alkynyl, cycloalkanyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heteroarylCycloalkyl, aryl or heteroaryl being unsubstituted or substituted by 1 to 4R6Substitution;
R6selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
wherein, R is contained simultaneouslybAnd RcIn the group of (A) RbAnd RcIs singly bound to the N atoms of the radicals or to the nitrogen atom to which they are bound to form a heterocycloalkyl radical which is unsubstituted or substituted by 1 to 3R7Substitution;
R7selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
m, n, p, q, and y are each independently 1,2, or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IA):
wherein the content of the first and second substances,
R4selected from:CORd,CONRbRc,CO2Rd,SO2Rdor SO2NRbRc;
R5Selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRcAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is unsubstituted or substituted with 1-3R5aSubstitution;
R5aselected from: h, D, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc(ii) a Wherein said alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1-3R5bSubstitution;
R5bselected from: h, D, halogen, cyano, ORa,SRa,NRbRc,CORd,CONRbRc,CO2Rd,SO2Rd,SO2NRbRc;
R8Selected from: h, D, alkyl, halogen, haloalkyl, ORa;
Ra,Rb,RcAnd RdEach selected from: h, D, alkyl, alkenyl, alkynyl, cycloakyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is unsubstituted or substituted with 1-4R6Substitution;
R6selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
wherein, R is contained simultaneouslybAnd RcIn the group of (A) RbAnd RcIs singly bound to the N atoms of the radicals or to the nitrogen atom to which they are bound to form a heterocycloalkyl radical which is unsubstituted or substituted by 1 to 3R7Substitution;
R7selected from: h, D, halogen, cyano, ORa,SRa,NRbRc,NRbCORd,NRbCONRbRc,CONRbRc,CO2Rd,NRbSO2Rd,NRbSO2NRbRc,SORd,SO2Rd,SO2NRbRcAlkyl, cycloakyl, heterocyclic alkanyl, aryl, or heteroaryl;
z is 1 or 2.
3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the compound is selected from the group consisting of:
n- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (difluoromethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-methyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-ethyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1-isopropyl-1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclopropyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-cyanocyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (aminomethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1- (hydroxymethyl) cyclobutyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1- (1-hydroxy-2-methylpropyl-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1- (1-amino-2-methylpropan-2-yl) -1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1H-pyrazol-4-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-4-yl) -2-pyridineamide
N- (1- (1- (1-acryloylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (1- (1- (1-acetylpiperidin-4-yl) azetidin-3-yl) -3- (difluoromethyl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
Methyl 4- (3- (4- (6- (1H-pyrazol-3-yl) -2-pyridineamide) -3- (difluoromethyl) -1H-pyrazol-1-yl) azetidin-1-yl) piperidine-1-carboxylate
N- (3- (difluoromethyl) -1- (1- (1-propionylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1-isobutyrylpiperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1- (2,2, 2-trifluoroethyl) -1H-pyrazol-4-yl) -2-pyridineamide
(S) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
(R) -6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
6- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (dimethylcarbamoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide
(S) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
(R) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxypropionyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxy-2-methylpropanoyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
N- (3- (difluoromethyl) -1- (1- (1- (methylsulfonyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -6- (1H-pyrazol-3-yl) -2-pyridineamide
6- (1- (2-cyanopropan-2-yl) -1H-pyrazol-4-yl) -N- (3- (difluoromethyl) -1- (1- (1- (2-hydroxyacetyl) piperidin-4-yl) azetidin-3-yl) -1H-pyrazol-4-yl) -2-pyridineamide.
4. A pharmaceutical composition consisting of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 in the manufacture of a medicament for inhibiting an IRAK family kinase.
6. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of a disease mediated by an IRAK family kinase.
7. The use according to claim 6, wherein the disease is an autoimmune disease; inflammatory diseases; pain disorders; respiratory, airway and lung diseases; lung inflammation and injury; pulmonary hypertension; gastrointestinal disorders; allergic diseases; infectious diseases; trauma and tissue injury disorders; fibrotic diseases; eye diseases; joint, muscle and bone diseases; skin diseases; kidney disease; diseases of the hematopoietic system; liver disease; oral diseases; metabolic diseases, heart diseases; vascular disease; a neuroinflammatory disorder; neurodegenerative diseases; sepsis; a genetic disease; and cancer.
8. The use according to claim 7, wherein the autoimmune and inflammatory diseases are selected from the group consisting of: systemic lupus erythematosus, lupus nephritis, arthritis, psoriasis, colitis, crohn's disease, atopic dermatitis, liver fibrosis, senile dementia, gout, protein-related periodic syndrome, chronic kidney disease or acute kidney injury, chronic obstructive pulmonary disease, asthma, bronchospasm, and graft-versus-host disease; the cancer is selected from: breast cancer, small cell lung cancer, non-small cell lung cancer, bronchoalveolar carcinoma, prostate cancer, bile duct cancer, bone cancer, bladder cancer, head and neck cancer, kidney cancer, liver cancer, cancer of gastrointestinal tissue, esophageal cancer, ovarian cancer, pancreatic cancer, skin cancer, testicular cancer, thyroid cancer, uterine cancer, cervical and vaginal cancer, leukemia, multiple myeloma, and lymphoma.
9. Use according to claim 6 or 7, characterized in that: the drug is used alone or in combination with other drugs; wherein the other drugs are preferably any one or a combination of at least two of small molecule drugs, monomer clone drugs, fusion protein drugs and anti-influenza DNA drugs.
10. A process for preparing a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, consisting of the steps of:
A. reacting nitropyrazole carboxylate A-1 with Boc-protected azetidinesulfonate A-2 to obtain A-3, wherein R1Is alkyl, R2Is alkyl or aryl;
B.A-3 with a reducing agent such as diisobutylaluminum hydride DIBAL-H to give aldehyde B-1;
the aldehyde group in C.B-1 is converted to difluoromethyl group using a fluorine reagent such as diethylaminosulfur trifluoride DAST to give C-1;
removing Boc in C-1 with an acid such as trifluoroacetic acid, and performing reductive amination with Boc-protected piperidone to obtain D-1;
E.D-1, wherein L is chlorine or OH, is removed with an acid, such as trifluoroacetic acid, and condensed with an acid chloride, or condensed with an acid with a condensing agent, such as HATU, to give E-1;
F.E-1 with a reducing agent, e.g. H2And Pd/C, reducing to obtain an amino compound F-1;
G. pyrazole boronic acid esters G-1 with 6-bromo-2-pyridinecarboxylic acid (X ═ H) or carboxylic acid esters (X ═ alkyl) G-2 over a palladium catalyst, for example Pd (PPh)3)4Coupled, then hydrolyzed with a base (when X ═ alkyl), such as NaOH, to give G-3;
H. the carboxylic acid G-3 is condensed with amino intermediate F-1 using a condensing agent, such as HATU, to provide compound IA of the present invention. If R in IA5When an amino group is present, R of G-3 condensed with F-15With cyano groups in the presence of a reducing agent, e.g. NaBH4/CoCl2/MeOH, reduction to give R5Compound IA containing an amino group;
I. alternatively, amino intermediate F-1 is condensed with pyridine carboxylic acid G-2 using a condensing agent, such as HATU, to provide I-1; then I-1 is reacted with the borate G-1 using a palladium catalyst, e.g. Pd (PPh)3)4Coupling to give compound IA of the invention;
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WO2016172560A1 (en) * | 2015-04-22 | 2016-10-27 | Rigel Pharmaceuticals, Inc. | Pyrazole compounds and method for making and using the compounds |
WO2016210036A1 (en) * | 2015-06-24 | 2016-12-29 | Bristol-Myers Squibb Company | Heteroaryl substituted aminopyridine compounds |
WO2018081294A1 (en) * | 2016-10-26 | 2018-05-03 | Rigel Pharmaceuticals, Inc. | Pyrazole amide compounds as irak inhibitors |
WO2018089199A1 (en) * | 2016-10-26 | 2018-05-17 | Rigel Pharmaceuticals, Inc. | Oxazole derivatives for use as irak inhibitors and method for their preparation |
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US9586948B2 (en) | 2012-10-08 | 2017-03-07 | Merck Sharp & Dohme Corp. | Inhibitors of IRAK4 activity |
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WO2016210036A1 (en) * | 2015-06-24 | 2016-12-29 | Bristol-Myers Squibb Company | Heteroaryl substituted aminopyridine compounds |
WO2018081294A1 (en) * | 2016-10-26 | 2018-05-03 | Rigel Pharmaceuticals, Inc. | Pyrazole amide compounds as irak inhibitors |
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